Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a)

被引：83

作者：

Stiekema, Lotte C. A. ^{[1
]}

Prange, Koen H. M. ^{[2
]}

Hoogeveen, Renate M. ^{[1
]}

Verweij, Simone L. ^{[1
]}

Kroon, Jeffrey ^{[1
]}

Schnitzler, Johan G. ^{[1
]}

Dzobo, Kim E. ^{[1
]}

Cupido, Arjen J. ^{[1
]}

Tsimikas, Sotirios ^{[3
,4
]}

Stroes, Erik S. G. ^{[1
]}

de Winther, Menno P. J. ^{[2
,5
]}

Bahjat, Mahnoush ^{[1
]}

机构：

[1] Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Med Biochem, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[3] Ionis Pharmaceut, 2855 Gazelle Ct, Carlsbad, CA 92008 USA

[4] Univ Calif San Diego, Sulpizio Cardiovasc Ctr, Vasc Med Program, 9434 Med Ctr Dr, La Jolla, CA 92037 USA

[5] LMU, IPEK, Inst Cardiovasc Prevent, Pettenkoferstr 9, D-80336 Munich, Germany

来源：

EUROPEAN HEART JOURNAL | 2020年 / 41卷 / 24期

关键词：

Lipoprotein(a); Apo(a)-antisense; PCSK9ab; Inflammation; Monocytes; Transcriptomics; BASE-LINE; RISK; PREDICTION; INNATE;

D O I：

10.1093/eurheartj/ehaa171

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a). Methods and results Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well ult as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C). Conclusion Potent Lp(a)-towering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).

引用

页码：2262 / 2271

页数：10

共 22 条

[1] Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo [J].

Bekkering, Siroon ;

van den Munckhof, Inge ;

Nielen, Tim ;

Lamfers, Evert ;

Dinarello, Charles ;

Rutten, Joost ;

de Graaf, Jacqueline ;

Joosten, Leo A. B. ;

Netea, Mihai G. ;

Gomes, Marc E. R. ;

Riksen, Niels P. .

ATHEROSCLEROSIS, 2016, 254 :228-236

[2] Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies A Mendelian Randomization Analysis [J].

Burgess, Stephen ;

Ference, Brian A. ;

Staley, James R. ;

Freitag, Daniel F. ;

Mason, Amy M. ;

Nielsen, Sune F. ;

Willeit, Peter ;

Young, Robin ;

Surendran, Praveen ;

Karthikeyan, Savita ;

Bolton, Thomas R. ;

Peters, James E. ;

Kamstrup, Pia R. ;

Tybjaerg-Hansen, Anne ;

Benn, Marianne ;

Langsted, Anne ;

Schnohr, Peter ;

Vedel-Krogh, Signe ;

Kobylecki, Camilla J. ;

Ford, Ian ;

Packard, Chris ;

Trompet, Stella ;

Jukema, J. Wouter ;

Sattar, Naveed ;

Di Angelantonio, Emanuele ;

Saleheen, Danish ;

Howson, Joanna M. M. ;

Nordestgaard, Borge G. ;

Butterworth, Adam S. ;

Danesh, John .

JAMA CARDIOLOGY, 2018, 3 (07) :619-627

[3] Effect of Nicotinic acid/Laropiprant in the lipoprotein(a) concentration with regard to baseline lipoprotein(a) concentration and LPA genotype [J].

Cenarro, Ana ;

Puzo, Jose ;

Ferrando, Juan ;

Mateo-Gallego, Rocio ;

Bea, Ana M. ;

Calmarza, Pilar ;

Jarauta, Estibaliz ;

Civeira, Fernando .

METABOLISM-CLINICAL AND EXPERIMENTAL, 2014, 63 (03) :365-371

[4] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease [J].

Clarke, Robert ;

Peden, John F. ;

Hopewell, Jemma C. ;

Kyriakou, Theodosios ;

Goel, Anuj ;

Heath, Simon C. ;

Parish, Sarah ;

Barlera, Simona ;

Franzosi, Maria Grazia ;

Rust, Stephan ;

Bennett, Derrick ;

Silveira, Angela ;

Malarstig, Anders ;

Green, Fiona R. ;

Lathrop, Mark ;

Gigante, Bruna ;

Leander, Karin ;

de Faire, Ulf ;

Seedorf, Udo ;

Hamsten, Anders ;

Collins, Rory ;

Watkins, Hugh ;

Farrall, Martin .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (26) :2518-2528

[5] Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease [J].

Bowman L. ;

Hopewell J.C. ;

Chen F. ;

Wallendszus K. ;

Stevens W. ;

Collins R. ;

Wiviott S.D. ;

Cannon C.P. ;

Braunwald E. ;

Sammons E. ;

Landray M.J. ;

Jiang L. ;

Armitage J. ;

Haynes R. ;

Maggioni A.P. ;

Angermann C.E. ;

Ertl G. ;

Wanner C. ;

Pedersen T. ;

Goto S. ;

Teramoto T. ;

Baigent C. ;

Barter P. ;

Chen Y. ;

Chen Z. ;

Gray A. ;

Mihaylova B. ;

Sleight P. ;

Tobert J. ;

Blaustein R. ;

DeLucca P. ;

Mitchel Y. ;

van Leijenhorst G. ;

Sandercock P. ;

DeMets D. ;

Kjekshus J. ;

Neuberger J. ;

Tonkin A. ;

Emberson J. ;

Granger C. ;

Colhoun H. ;

Barton J. ;

Bray C. ;

Dayanandan R. ;

Knott C. ;

Lay M. ;

Murphy K. ;

Wincott E. ;

Achiri P. ;

Barry S. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 377 (13) :1217-1227

[6] Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury [J].

Imai, Yumiko ;

Kuba, Keiji ;

Neely, G. Greg ;

Yaghubian-Malhami, Rubina ;

Perkmann, Thomas ;

van Loo, Geert ;

Ermolaeva, Maria ;

Veldhuizen, Ruud ;

Leung, Y. H. Connie ;

Wang, Hongliang ;

Liu, Haolin ;

Sun, Yang ;

Pasparakis, Manolis ;

Kopf, Manfred ;

Mech, Christin ;

Bavari, Sina ;

Peiris, J. S. Malik ;

Slutsky, Arthur S. ;

Akira, Shizuo ;

Hultqvist, Malin ;

Holmdahl, Rikard ;

Nicholls, John ;

Jiang, Chengyu ;

Binder, Christoph J. ;

Penninger, Josef M. .

CELL, 2008, 133 (02) :235-249

[7] Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction [J].

Kamstrup, Pia R. ;

Tybjaerg-Hansen, Anne ;

Steffensen, Rolf ;

Nordestgaard, Borge G. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2009, 301 (22) :2331-2339

[8] Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients [J].

Landray, Martin J. ;

Haynes, Richard ;

Hopewell, Jemma C. ;

Parish, Sarah ;

Aung, Theingi ;

Tomson, Joseph ;

Wallendszus, Karl ;

Craig, Martin ;

Jiang, Lixin ;

Collins, Rory ;

Armitage, Jane .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (03) :203-212

[9] PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia [J].

Moens, Sophie J. Bernelot ;

Neele, Annette E. ;

Kroon, Jeffrey ;

van der Valk, Fleur M. ;

Van den Bossche, Jan ;

Hoeksema, Marten A. ;

Hoogeveen, Renate M. ;

Schnitzler, Johan G. ;

Baccara-Dinet, Marie T. ;

Manvelian, Garen ;

de Winther, Menno P. J. ;

Stroes, Erik S. G. .

EUROPEAN HEART JOURNAL, 2017, 38 (20) :1584-1593

[10] DAMPening Inflammation by Modulating TLR Signalling [J].

Piccinini, A. M. ;

Midwood, K. S. .

MEDIATORS OF INFLAMMATION, 2010, 2010

← 1 2 3 →